Shikonin inhibits prostate cancer cells metastasis by reducing matrix metalloproteinase-2/-9 expression via AKT/mTOR and ROS/ERK1/2 pathways
Shikonin inhibits prostate cancer cells metastasis by reducing matrix metalloproteinase-2/-9 expression via AKT/mTOR and ROS/ERK1/2 pathways
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DOI：
10.1016/j.intimp.2014.05.026
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发表时间：
2014-08-01
影响因子：
5.6
通讯作者：
Chen, Fuxing
中科院分区：
文献类型：
--
作者：
Chen, Yongqiang;Zheng, Lu;Chen, Fuxing
转移是影响前列腺癌疗效的重要因素之一。紫草素是从中药紫草中分离得到的一种具有活性的萘醌类化合物，在体内和体外均具有多种抗癌活性。然而，紫草素的抗癌活性的机制并没有完全阐明对前列腺癌细胞。在本研究中，我们的目的是探讨紫草素对前列腺癌细胞的潜在影响和紫草素发挥其作用的潜在机制。通过细胞增殖、细胞周期、迁移和侵袭实验，我们发现紫草素能有效抑制PC-3和DU 145细胞的生长，使细胞周期阻滞在G2期，并呈剂量依赖性地抑制细胞的转移。紫草素抑制PC-3和DU 145细胞转移的机制可能与抑制基质金属蛋白酶-2（MMP-2）和MMP-9的表达和活化有关。紫草素可剂量依赖性地降低AKT和mTOR的磷酸化水平，诱导细胞外信号调节激酶（ERK）、p38丝裂原活化蛋白激酶（MAPK）和c-Jun N末端激酶（JNK）磷酸化。进一步的机制研究表明，紫草素还诱导活性氧（ROS）的产生，这是由ROS清除剂二硫苏糖醇（DTT）逆转。DTT可逆转紫草素诱导的ERK 1/2的激活，从而维持MMP-2和MMP-9的表达，恢复细胞转移。紫草素通过AKT/mTOR和ROS/ERK 1/2途径降低MMP-2/-9表达，抑制前列腺癌细胞的侵袭和迁移，为前列腺癌的治疗提供了一种新的替代药物。(C)2014爱思唯尔有限公司版权所有。
Metastasis is one of the most important factors related to prostate cancer therapeutic efficacy. In previous studies, shikonin, an active naphthoquinone isolated from the Chinese medicine Zi Cao, has various anticancer activities both in vivo and in vitro. However, the mechanisms underlying shikonin's anticancer activity are not fully elucidated on prostate cancer cells. In the present study, we aimed to investigate the potential effects of shikonin on prostate cancer cells and the underlying mechanisms by which shikonin exerted its actions. With cell proliferation, flow cytometric cell cycle, migration and invasion assays, we found that shikonin potently suppressed PC-3 and DU145 cell growth by cell cycle arrest at the G2 phase and metastasis in a dose-dependent manner. Mechanically, we presented that shikonin could suppress the metastasis of PC-3 and DU145 cells via inhibiting the matrix metalloproteinase-2 (MMP-2) and MMP-9 expression and activation. In addition, shikonin significantly decreased the phosphorylation of AKT and mTOR in a dose-dependent manner while it induced extracellular signal-regulated kinase (ERK), p38 mitogen activated protein kinase (MAPK) and c-Jun N terminal kinase (JNK) phosphorylation. Further investigation of the underlying mechanism revealed that shikonin also induced the production of reactive oxygen species (ROS) that was reversed by the ROS scavenger dithiothreitol (DTT). Additionally, DTT reversed the shikonin induced activation of ERK1/2, thereby maintaining MMP-2 and MMP-9 expression and restoring cell metastasis. Together, shikonin inhibits aggressive prostate cancer cell migration and invasion by reducing MMP-2/-9 expression via AKT/mTOR and ROS/ERK1/2 pathways and presents a potential novel alternative agent for the treatment of human prostate cancer. (C) 2014 Elsevier B.V. All rights reserved.